PROJECT SUMMARY: Project 1 ? Neurotoxicity Studies by the Iowa Superfund Research Program demonstrate that inhalation of indoor air, especially in U.S. schools contaminated with polychlorinated biphenyls (PCBs), represents a current public health concern for U.S. adolescents. Although the adolescent brain is vulnerable to the toxicity of PCBs and their metabolites, information regarding the neurotoxicity of human metabolites of airborne PCBs?which differ significantly from those formed in rodents?is currently not available. There is, therefore, a critical need to: 1) establish mechanisms by which human metabolites of PCBs affect neurochemistry (i.e., toxic neurotransmitter metabolites) and subsequent behavioral outcomes; and 2) determine how metabolism of airborne PCBs and their metabolites in the brain represents a key event in PCB-mediated neurotoxicity in adolescents exposed to PCBs. The objective of this project is to inform future risk assessment by defining the link between neurotoxic PCB metabolites present in the brain and neurotoxic outcomes following exposure during adolescence. Our central hypothesis is that, in addition to the parent airborne PCBs, metabolites formed in humans are present in the brain and serve as risk factors for altered neurodevelopment during adolescence. We propose that PCBs, and especially their metabolites, adversely affect neurotransmitter homeostasis. This hypothesis is based on preliminary studies showing that metabolites of airborne PCBs: a) are present in the rodent brain; b) cause oxidative stress in vitro and in vivo; c) alter neurotransmitter homeostasis in dopaminergic neurons in culture, producing ROS and toxic catecholaldehydes; and d) undergo further metabolism to potentially toxic metabolites in the brain. Guided by these preliminary data, the novel hypothesis will be tested by 1) identifying cellular sites and targets of airborne PCB metabolites vs. parent compounds responsible for neurotoxicity in vitro; 2) characterizing the region- specific biotransformation of PCBs and PCB metabolites with in vitro models and in the adolescent rat brain in vivo; and 3) determining the effects of human metabolites of airborne PCBs on biochemical markers of PCB neurotoxicity and behavioral outcomes in rats exposed throughout adolescence in vivo. The proposed research is innovative because it determines how the disruption of dopamine balance by PCB metabolites disturbs dopamine levels and/or produces toxic dopamine metabolites detrimental to the brain in adolescence, a period of vulnerability; and studies localized metabolism in the brain, thus challenging the scientific paradigm that PCBs are either resistant to metabolism or metabolized only in the liver. Outcomes of the proposed studies will elucidate the contributions of airborne PCBs and their metabolites to, and their mechanisms of action in, neurotoxic responses. Thus, the successful completion of this research will impact public health by providing fundamental, mechanistic insights urgently needed to advance the human risk assessment of exposure to PCBs, with the ultimate goal of preventing or mitigating adverse outcomes following exposure to this class of Superfund chemicals.